This project will determine whether novel patterns of dose and dose-rate can improve radiation therapy of human cancer when based on mechanisms that determine radiosensitivity in human tumor cells. We have made three novel observations in a system of genetically-defined human colorectal tumor cells: 1) two distinctly different patterns of response to acute and protracted irradiation (radioresponse phenotypes) are observed and p53 predicts the pattern of response observed in a specific cell line; 2) protracted irradiation alters the radiosensitivity in tumor cells through two distinct mechanisms, with some cells becoming more resistant and some more sensitive depending on the specific cell type; 3) p21- modulated apoptosis has no effect on in vitro radio-sensitivity but modifies tumor response. Importantly, other radio-resistant tumor cells such as glioblastomas can be dramatically sensitized by protracted irradiation and if this sensitizing process can be translated into the clinic it might have significant impact. These data taken together suggest that radiotherapy of tumors, to be optimally effective, should exploit the particular radio-response phenotype of the constituent tumor cells. We have used these several observations to construct a new model that we term the alpha-omega model. This model presents a new analytical structure for planning radiation therapy protocols that use combinations of dose and dose-rate to achieve optimal effects. We now propose to use the alpha omega model to suggest patterns of acute and protracted irradiation hypothesized to produce maximum cell kill in vitro and test these predictions experimentally. Project 2 will provide data that describe the effects of tumor microenvironment on mechanisms of radiosensitivity including radio-sensitization by protracted irradiation. These data when combined with results from this project will be used to propose radiotherapy protocols that will maximize response in experimental tumors. The several cores and projects will together test these hypotheses and if successful, translate these into the clinic. This project will test the hypothesis: Radiotherapy protocols of combined acute and protracted irradiation will improve response in cells and tumors in such protocols are based on the radio- response phenotype of the constituent cells.